Hemostasis, the arrest of bleeding from an injured blood vessel, requires the coordinated regulation of vascular, platelet, and plasma factors to eventually form a hemostatic seal or a blood clot. In normal hemostasis, collective activity activity of these factors is counterbalanced by regulatory mechanisms that limit the accumulation of platelets and fibrin in the area of injury.
In normal hemostasis, the process of clot formation (blood coagulation) and clot dissolution (fibrinolysis) is delicately balanced. A slight imbalance between the processes of clot formation and dissolution can lead to excessive bleeding or thrombosis, and there are several disease states related to abnormal hemostasis. For example, abnormal thrombus formation in the coronary arterial vasculature due to the rupture of an established atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Moreover, treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA) is often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. Also, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature, which can result in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Additionally, disseminated intravascular coagulopathy is characterized by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure. Disseminated intravascular coagulopathy commonly occur within both vascular systems during septic shock, certain viral infections and cancer.
Thus, pathogenic thrombosis in the arterial vasculature is a major clinical concern in today's medicine. It is the leading cause of acute myocardial infarction which is one of the leading causes of death in the western world. Recurrent arterial thrombosis also remains one of the leading causes of failure following enzymatic or mechanical recanalization of occluded coronary vessels using thrombolytic agents or percutaneous transluminal coronary angioplasty (PTCA), respectively [Ross, A. M., Thrombosis in Cardiovascular Disorder, p. 327, W.B. Saunders Co., Fuster, V. and Verstraete, M. eds. 1991); Califf, R. M. and Willerson, J. T., Id. at p 389]. In contrast to thrombotic events in the venous vasculature, arterial thrombosis is the result of a complex interaction between fibrin formation resulting from the blood coagulation cascade and cellular components, particularly platelets, which make up a large percentage of arterial thrombi. Heparin, the most widely used clinical anticoagulant administered intravenously, has not been shown to be universally effective in the treatment or prevention of acute arterial thrombosis or rethrombosis [Prins, M. H. and Hirsh, J., J. Am. Coll. Cardiol., 67: 3A (1991)].
Besides the unpredictable, recurrent thrombotic reocclusion which commonly occurs following PTCA, a profound restenosis of the recanalized vessel occurs in 30 to 40% of patients 1 to 6 months following this procedure [Califf, R. M. et al., J. Am. Coll. Cardiol., 17: 2B (1991)]. These patients require further treatment with either a repeat PTCA, or coronary artery bypass surgery, to relieve the newly formed stenosis. Restenosis of a mechanically damaged vessel is not a thrombotic process but instead is the result of a hyperproliferative response in the surrounding smooth muscle cells which over time results in a decreased luminal diameter of the affected vessel due to increased muscle mass. Id. As for arterial thrombosis, there is currently no effective pharmacologic treatment for the prevention of vascular restenosis following mechanical recanalization.
Thus, there is a need for specific anti-thrombotic agents. Also, there is a need for anti-thrombotic agents that selectively inhibit factors in either the extrinsic pathway or the intrinisic pathway, while leaving the other pathway unaffected.